• Ramya Thota, Douglas B Johnson, and Jeffrey A Sosman.
• Vanderbilt University Medical Center, Department of Medicine , 777 PRB, 2220 Pierce Ave, Nashville, TN 37232 , USA +1 615 322 8131 ; +1 615 343 7602 ; jeff.sosman@Vanderbilt.Edu.
• Expert Opin Biol Ther. 2015 May 1;15(5):735-47.

IntroductionAberrant MAPK pathway signaling is a hallmark of melanoma. Mitogen/extracellular signal-regulated kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF(V600) mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib.Areas CoveredIn this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma.Expert OpinionTrametinib is a novel oral MEK inhibitor with clinical activity in BRAF(V600) mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway.

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